In order to assess the clinical and pathologic significance of the immunologic characterization of human malignant lymphomas, biopsy tissues are obtained from patients referred to the Clinical Center for treatment and/or diagnosis. Biopsies are obtained with patient permission prior to therapy and processed in the Hematopathology Section. Paraffin blocks from biopsies performed outside the NIH are obtained for immunophenotypic characterization. The neoplastic cells are characterized as to their origin from T cells, NK cells, B-cells, or histiocytes, and in addition can be identified as belonging to specific developmental and functional subpopulations. Immunophenotypic data are correlated with histologic and clinical findings, with the goal of defining distinctive clinicopathologic entities. The relevance of immunophenotype as correlated with response to therapy is explored. Immunophenotypic and morphologic data are correlated with molecular and cytogenetic findings, to define the pathogenesis of disease entities. This information is used to define new clinicopathologic entities, and to further refine the definition of currently recognized diseases. It is also used as a basis for immunotherapy, either alone or in concert with conventional chemotherapy and radiotherapy.The functional repertoire of neoplastic lymphoid cells is studied by evaluating the production of chemokines and cytokines using molecular and immunohistochemical methods. These data are correlated with histological and clinical parameters. In 1998-1999 we defined the pathologic and immunophenotypic spectrum of lymphoproliferative lesions associated with the human autoimmune lymphoproliferative syndrome (ALPS). In addition, we recognized that patients with ALPS are at increased risk for the development of B-cell lymphomas. The risk of lymphoma may be secondary to primary defects in lymphocyte apoptosis, or a consequence of lymphocyte expansion related to excessive cytokine production. Levels of IL-4, IL-5 and IL-10 are markedly increased in these patients.We defined the histologic and immunophenotypic criteria for the definition of marginal zone lymphomas (MZL) in lymph nodes. These lymphomas uncommonly present in lymph nodes, and their relationship to extranodal marginal zone lymphomas of MALT type is poorly understood. We showed that in approximately 50% of patients with nodal marginal zone lymphomas, extranodal disease can be identified, sometimes many years before or after the nodal presentation. However, in 50% of patients with nodal MZL, lymphoma is restricted to nodal sites. Rare nodal MZL lymphomas resembling so-called splenic MZL can also be seen. Further studies were conducted to define the immunophenotypic and molecular features of nasal NK/T cell lymphomas. In addition, rare peripheral T-cell lymphomas containing EBV-positive Reed-Sternberg like cells were identified. These biopsies may be mistaken for Hodkgins disease, based on morphologic and immunophenotypic similarities. Using laser capture microdissection techniques, the Reed-Sternberg-like cells contain rearranged immunoglobulin genes and are polyclonal. Progression to classical Hodgkins disease was not seen. The expansion of EBV-positive cells which express LMP-1 is felt to be related to the underlying abnormal immune state associated with the T-cell lymphoma. - lymphokines, lymphoma, monoclonal antibodies, T lymphocytes, B-lymphocyte, - Human Tissues, Fluids, Cells, etc.